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Burns et al. Altered filamin A enables Aβ signaling

Aβ, the altered FLNA conformation exists not only in kinases to hyperphosphorylate tau protein [30,32,33,52] .
postmortem human AD brain and in triple transgenic We know that the linkage of altered FLNA is
(3xTg) AD mice, but also in ICV Aβ 42 -infused wildtype required for this Aβ signaling pathway because
mice and in Aβ 42 -treated postmortem human control the novel drug candidate PTI-125 prevents the
brain [13] . FLNA-α7nAChR linkage and greatly reduces tau
hyperphosphorylation [13,15] . Hyperphosphorylated
This altered form of FLNA was evidenced by a shift tau loses its ability to stabilize microtubules and
in isoelectric focusing point (pI) from 5.9 in the native dissociates from them, thereby increasing the pool
state to 5.3 in postmortem human AD brain or brains of free phosphorylated tau that eventually appears in
of mouse models [13] . An altered pI can indicate an neurofibrillary tangles. We suggest that the signaling
altered conformation, reflecting changes in hydrogen of Aβ 42 via α7nAChR contributes prominently to a
bonding, charge-charge interactions or accessibility variety of AD-related neuropathologies in addition
of ionizable residues within the molecule [48-50] . In to, or perhaps elicited by, tau hyperphosphorylation
this case, the shifted pI is resistant to complete because these additional neuropathologies are also
dephosphorylation by alkaline phosphatase. Hence, reduced by PTI-125’s disruption of Aβ 42 ’s signaling
unlike the proteopathies of tau and alpha-synuclein, via α7nAChR [13,15] . Alternatively, they may be related
the altered conformation of FLNA is not due to to the neuroinflammatory signaling that is also
changes in phosphorylation state. Further studies are disrupted by PTI-125 as discussed below. An obvious
needed to reveal the details of FLNA’s conformational consequence of the toxic signaling through α7nAChR
change and whether altered FLNA is unique to AD. is that the normal function of α7nAChR is impaired.
Because α7nAChR is an upstream regulator of the
The induction of the altered conformation by Aβ 42 may N-methyl-D-aspartate receptor (NMDAR) [53,54] , the
suggest a direct interaction or some sort of cross- impaired NMDAR signaling in AD brain and 3xTg AD
protein templating by Aβ 42 . However, Aβ 42 and FLNA mice is very likely related to the impaired signaling
do not directly interact because neither protein can be via α7nAChR. This assertion is supported by the
co-immunoprecipitated with the other (our unpublished improvement in signaling function of both receptors by
[13,15]
observations). Although it is tempting to presume PTI-125 . Aβ 42 ’s signaling to hyperphosphorylate
that FLNA must be in its altered conformation to tau also contributes to eventual formation of Aβ
[55,56]
associate with α7nAChR, we hypothesize that it is deposits and tau-containing neurofibrillary lesions ,
FLNA’s transmembrane recruitment to this receptor, because disrupting this signaling via PTI-125 markedly
induced by Aβ 42 ’s extracellular binding, that changes reduces both Aβ deposits and neurofibrillary lesions in
[13,15]
FLNA’s conformation. Aβ 42 binds α7nAChR with 3xTg AD mice or ICV Aβ 42 -infused wildtype mice .
high femtomolar affinity, the highest known binding Finally, reiterating the improved receptor function
by PTI-125 and implicating this toxic Aβ signaling
affinity of Aβ 42 . Interestingly, prevention of the FLNA pathway in cognitive impairment, PTI-125 also
linkage to α7nAChR by FLNA-binding compound PTI- improved working and spatial memory and nesting
125 decreases Aβ 42 ’s affinity for this receptor 1,000- behavior abnormalities in 3xTg AD mice [13] .
10,000-fold, illustrating that FLNA enables not only
Aβ 42 ’s toxic signaling but also its high-affinity binding
for α7nAChR [15] . Although this observation appears ALTERED FLNA ENABLES Aβ-INDUCED
to suggest that altered FLNA is responsible for Aβ 42 ’s NEUROINFLAMMATION
binding, we propose a dynamic, sequential process:
(1) Aβ 42 binds α7nAChR to induce FLNA recruitment; The proteopathy of FLNA enables a second toxic
(2) recruitment alters FLNA’s conformation; and (3) signaling pathway of Aβ: its activation of the innate
FLNA’s altered form secures (locks in) an ultra-high immune receptor TLR4 [13,15] . Aβ 42 binds the CD14
affinity Aβ 42 -α7nAChR interaction. The reasoning co-receptor [14] , complexed with TLR4, to induce an
behind this hypothesis is that Aβ 42 induces both the aberrant FLNA linkage to TLR4 [13,15] , which appears
aberrant FLNA conformation and its recruitment to to reciprocally enable a sustained Aβ-mediated
α7nAChR (either by ICV Aβ 42 infusion to wildtype mice TLR4 activation [Figure 2]. Hence, the FLNA-TLR4
or by in vitro Aβ 42 incubation of postmortem control linkage, allowing Aβ activation of TLR4, promotes
brain) [13,15] and that Aβ 42 and FLNA do not themselves persistent inflammatory cytokine release and elicits
interact. neuroinflammation characteristic of AD. As with
α7nAChR, native FLNA in control brains does not
Enabled by FLNA, Aβ 42 , in monomeric or small associate with TLR4, unless treated with Aβ 42 by ICV
oligomeric form [51] , signals via α7nAChR to activate infusion to wildtype mice or by in vitro incubation of

266 Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ December 8, 2017